Clinical and experimental literature have rapidly converged to demonstrate that sleep and circadian dysfunction play an integral role in the onset and maintenance of a broad spectrum of chronic diseases. Sleep dysfunction is especially common among patients with neuropsychiatric disorders, which is the leading contributor of disease burden in the United States, more than twice as much as cardiovascular disease. Epidemiological data demonstrates that sleep disruption precedes and often predisposes people to anxiety, depression, and PTSD, suggesting that these complex traits are highly intertwined. Addressing the complexity of sleep and stress phenotypes requires novel approaches that leverage and integrate multiple forms of data. My proposal focuses on identifying causal molecular networks common to sleep and stress traits in order to investigate novel disease mechanisms and therapeutic strategies relevant to neuropsychiatric disorders. With an exhaustive phenotypic assay (479 sleep and stress traits) and an integrated multi-scale computational approach, we will leverage the complexity of these traits to probe how molecular pathways naturally interact as a coordinated unit, rather than how they react when they are artificially manipulated. By integrating genetic, gene expression, and co-expression data from F2 mouse populations (>100 mice), we can use Bayesian reconstruction to identify molecular subnetworks that act as causal regulators of stress and sleep phenotypes. Because of the complexity of sleep and stress traits, it is imperative that we understand individual genes in the context of polygenic networks and treat phenotypes as emergent properties of these networks. By understanding how these molecular networks act as sensors and drivers of phenotypes, we can then appropriately consider targets for pharmacological interventions and utilize novel computational strategies for repurposing drugs. We anticipate that this work will provide the foundation for future in vivo studies related to depression, anxiety, stress susceptibility (PTSD), and sleep.